Methobromide and hydrochloride of 1-ethyl-3-pyrrolidyl benzilate



United States Patent 3,301,869 METHOBROMIDE AND HYDROCHLORIDE 0F1-ETHYL-3-PYRROLIDYL BENZILATE Carl D. Lunsford, Richmond, Va., assignorto A. H.

Robins. Company, Inc., Richmond, Va., a corporation of Virginia NoDrawing. Filed May 16, 1960, Ser. No. 29,156 2 Claims. (Cl. 260-326.3)

This application is a continuation-in-part of Serial No. 666,250, filedJune 17, 1957, now abandoned, and of Serial No. 795,598, filed February26, 1959, and now Patent No. 2,956,062.

The present invention relates to esters of amino alcohols, moreparticularly certain esters of N- or l-substituted 3-pyrrolidinols.These novel compounds are specifically identified as the N- or1-substituted-3-pyrrolidyl benzilates. The concept constituting thepresent invention is illustrated by the following structural formula:

phenyl wherein R is a hydrocarbon radical, such as alkyl, cycloalkyl andaralkyl.

Nontoxic organic and inorganic acid addition salts of the compoundshaving the general structural formula shown above may be readilyprepared as illustrated in the examples below and include salts formedwith such inorganic and organic acids as hydrochloric, hydrobromic,hydriodic, sulfuric, sulfamic, phosphoric, acetic, glycolic, succinic,maleic, malic, citric, tartaric, ascorbic, benzoic, cinnamic, mandelic,benzilic, diphenylacetic and the like.

Quaternary ammonium salts such as alkyl salts cycloalkyl salts, aralkylsalts, and the like, of the organic bases illustratedin the generalstructural formula appearing above may be readily formed by treatment ofthe organic bases with the appropriate quaternary salt formingsubstances, which include, for example, methyl chloride, methyl bromide,methyl iodide, methyl sulfate, methyl benzenesulfonate, methylp-to-luenesulfonate, ethyl chloride, ethyl bromide, ethyl iodide,n-propyl chloride, n-propyl bromide, npropyl iodide, isopropyl bromide,n-butyl chloride, n-butyl bromide, isobutyl bromide, sec.-butyl bromide,n-amyl bromide, n-hexyl chloride, benzyl chloride, benzyl bromide, andethyl sulfate, yielding respectively the methochloride, methobromide,methiodide, methosulfate, methobenzenesulfonate,methop-toluenesulfonate, ethochloride, ethobromide, ethiodide,n-propochloride, n-propobrornide, n-propiodide, is-opropobromide,n-butocblo-ride, n-butobromide, isobutobromide, sec.-butobromide,n-amobromide, n-hexochloride, benzochloride, benzobromide, ethosulfate,etc.

In the structural formula given above, the asterisk serves to point outthe asymmetric carbon atom present in the compounds of the invention.The two separate stereoisomers, or optically active forms, are includedwithin the scope of the present invention. Resolution of the opticallyactiveforms may be accomplished by combining the mixture ofstereoisomers with an optically active organic acid and separating byfractional crystallization.

Evaluation of the compounds of the invention by standard pharmacologicaltests has indicated their utility as inhibitors of gastrointestinalmotility, comparing favorably in potency with methantheline bromide. Thecompounds are predominantly antagonists of acetylcholine.

' monium salts.

substituted compounds indicated greater activity and are Patented Jan.31, 1967 The present invention is characterized by a particularesterification of a secondary hydroxyl attached directly to a ringcarbon in the three position of the pyrrolidine ring. The prior art intowhich the compounds of the present invention fall can be distinguished.United States Patent 2,655,511 to Woodrulf describes N- or l-pyrrolidylesters where the alkanol group is extra-cyclic to the pyrrolidine ring(where there is a methylene bridge attached to the heterocyclicnitrogen); United States Patent 2,695,301 to Blicke teaches benzilatesproceeding from the two position of the pyrrolidine ring but differingfrom the present invention in that the hydroxyl esterified is primaryand extra cyclic; while United States Patent 2,735,847 to Blickedescribes diphenylacetates proceeding from the N- or l-position in thepyrrolidine ring and involves extra-cyclic esterification.

Therefore, it is an object of this invention to provide novel benzilatesof 3-pyrrolidinols.

It is a further object of the present invention to provide such esterswherein the 3-pyrrolidine portion of the molecule is substituted in theN- or l-position.

It is an additional object of the present invention to provide novelacetylcholine antagonists having a high degree of activity andsatisfactory activity when compared with known compounds currently inuse as inhibitors of gastrointestinal motility.

Other objects of the invention will become apparent to those skilled inthe art to which this invention pertains.

The new compounds include the benzilates of 3-pyrrolidinols wherein theN- or l-position of the pyrrolidine ring is substituted by a hydrocarbonradical such as straight or branchedchain alkyl, cycloalkyl, aralkyl andthe like, preferably lower-alkyl.

The term lower-alkyl is defined to include straight and branched-chainradicals of l-6 carbon atoms inclusive and includes such substituents asmethyl, ethyl, isopropyl, tertiary butyl, isoamyl and the like. The termcycloalkyl is defined to include primarily cyclic alkyl radicalscontaining 5 to 8 carbon atoms inclusive and encompasses suchsubstituents as cy-clohexyl, cyclopentyl, methyl cyclohexyl, ethylcyclopentyl, dimethyl cyclohexyl, and cycloheptyl. Included in the termaralkyl are such radicals as lower alkylsubstituted mono-carbocyclicaryl compounds such as benzyl, phenethyl, phenpropyl and the like.Preferably, R is a hydrocarbon radical containing less than 8 carbonatoms and is selected from the group consisting of lower-alkyl,cycloalkyl and aralkyl. On the other hand, the organic radical of thequaternary ammonium salts of the invention may be, for example any ofthe specific radicals, or types of radicals, e.g., lower-alkyl,cycloalkyl, or aralkyl, enumerated in this paragraph, the anion of thequaternary amonium salt being, for example, halogen, e.g., chloro,nitr-o (N0 sulfate (S0 or any other anion enumerated in the precedingparagraphs of this specification relating to such quaternary salts.

Generally, for reasons of activity, the esters of this invention arepreferred in the form of their nontoxic pharmaceutically acceptable acidaddition and quaternary am- Generally also, the N- or l-lower-alkyltherefore preferred. Among specifically preferred compounds are:1-methy1-3-pyrrolidyl benzilate methobromide 1-methyl-3-pyrrolidylbenzilate hydrochloride 1-ethyl-3-pyrrolidyl benzilate hydrochloride,and 1-ethyl-3-pyrrolidyl benzilate methobromide.

Since the alpha carbon of the acetate group is substituted by a hydroxylradical, the compounds may alternatively be viewed either as benzilatesor phenyl-substituted 'mandelates. The esters of the present inventionmay be rolidinol of the formula:

wherein R is as indicated above, with an alpha-phenylmandelic [benzylic]acid compound of the formula:

phenyl phenyl( ]C OB 6H wherein B is hydroxy, halogen or lower-alkoxy.

When B is lower-alkoxy, the transesterification reaction is conducted inthe presence of a sodium metal catalyst until the theoretical amount oflower alkanol separates. With this exception, the reaction conditionsare similar for all variants of starting compounds, i.e., the reactants,used in approximately equimolar amounts, are heated at refluxtemperatures for periods of at least about one hour and usually from oneto two hours, preferably using a hydrocarbon solvent as the reactionmedia. The resulting reaction product is extracted with dilute mineralacid, e.g., hydrochloric acid, and the resulting extract basified (e.g.,with aqueous sodium hydroxide) to yield the free base upon extractionwith the appropriate solvent. The acid addition salts and quaternarysalts are produced from the base by reaction in solvent of the base andthe appropriate acid or quaternizing reagent.

The preparation of starting N-substituted-3-pyrrolidinols used in thepresent invention has been previously de- The hydrochloride wasprecipiated from an ethereal solution of the base with ethereal hydrogenchloride and crystallized from a dry ethyl acetate-ethanol mixture; M.P.1915-193 C.

The methobromide quaternary salt precipitated from a butanone solutionof the base and excess methyl bromide after standing for 24 hours. Itwas crystallized from a butanone-rnethanol mixture; M.P. 169l70.5 C.

In the same manner as given in the preceding example, by reacting theappropriate 1-hydrocarbon substituted- 3-pyrrolidinol with theappropriate esterifying agent, additional compounds within the scope ofthe general structural formula are prepared.

Representative products prepared from the chosen starting materials areas follows:

l-phenethyl-3-pyrro1idyl benzilate hydroiodide 1-phenethyl-3-pyrrolidylbenzilate sulfate 1-phenpropyl-3-pyrrolidyl benzilate succinate1-dimethylbenzyl-3-pyrrolidyl benzilate citrate1-cycloheptyl-3-pyrrolidyl benzilate methobromide1-phenethyl-3-pyrrolidyl benzilate tartrate 1-phenpropyl-3-pyrrolidylbenzilate benzoate 1-phenethyl-3-pyrrolidyl benzilate methochloride1-phenpropyl-3-pyrrolidyl benzilate ethyl iodidel-di-methylbenzyl-3-pyrrolidyl benzilate ethosulfate1-phenethyl-3-pyrroliclyl benzilate l-phenpropyl-3-pyrrolidyl benzilateimethobenzene sulfonate.

Other compounds within the scope of the invention are shown in Table X.In each instance the free base as well :as the indicated acid additionor quaternary salt was prepared.

TABLE X ph enyl C H2NR phenyl-OO O-OC H 0 H O H2O H2 R Salt Calculatedfor Percent Found M..W. M. P., C.

CiaHziNOs-HCL" 10.19 10. 12 347. 83 176-177 Cl'I23NO3'IIG1 9. 80 9. 79361. 86 148-149 C2lI-l25NO -HCL 9. 43 9.19 375. 88 191. 5-193C72H27NO3-IICl 9. 09 9.16 389.91 179-180. 5 Czsl'lerNoz-l-lclnt 9. 00 8.86 389. 91 155-155. 5 C 11 LmNO -HCl..- 8. 13 8.16 485. 95 201. 5-206. 5C251I NO3- 1101... 8. 36 8.16 423. 92 154. 5-150 1:1 CIIQBC'g0I'12lNO3-BI' 10. (5G 19. 79 406. 32 211-212. 5 CHaBr CMHQGNOQBLMH19.01 19. 420. 34 150-152 e CHaBr. C22H2sNOs-Br- 18. 48 18. 33 432. 36169-170. 5 ClIaBr czaHaoNos-Brnut 17. 82 17.97 448. 40 170-180. 5 CHBrNn CQQHmNOa-BLMH 17. 82 17.62 448. 40 153. 5-155 01131313.--C2aHa2NOa-Br 16. 84 16. 48 474. 46 185. 5-187 CtIIaC z CHaBr C2sHzsNOaBr16. 57 16. 23 482. 41 186-187. 5

scribed in United States Patents 2,830,997 and 2,838,521 of Lunsford.

The following example illustrates the preparation of the compounds ofthe present invention, but is in no way to be construed as limiting:

All compounds may be prepared by the alternative modifications of theprocedure using either the acid or acid .chloride, or a loWer-alkylester of the acid, e.g., methyl.

Example-1-is0pr0pyl-3-pyrr0lidyl benzilate A mixture of 72 grams (0.3mole) of methyl benzilate and 39 grams (0.3 mole) of1-isopropyl-3-pyrrolidinol in 400 milliliters of heptane was refluxedunder a Dean and Stark moisture trap with the addition of four 0.1 grampieces of sodium at one hour intervals. When the theoretical amount ofmethanol had separated, the solution was extracted .with 3 Nhydrochloric acid. The acid extract was basified with sodium hydroxidesolution and extracted with ether. The other layer was washed, driedover sodium sulfate and concentrated, and the residue fractionallydistilled :at reduced pressure. Yield: grams (54 percent); B..P. .14l143C. at 0.2 mm.

In evaluating the compounds of the invention pharmacologically, thefollowing experimental testing procedure was utilized.

Isolated guinea pig ileum studies Guinea pigs were killed by a blow onthe head. The ileum was removed and terminal segments were suspended ina ml. smooth muscle bath containing Tyrodes solution which wasmaintained at 37 C. The bath was aerated by bubbling a continuous streamof oxygen therethrough. Intestinal activity was recorded by a balancedink-writing lever yielding five-fold magnification on a Gorrell andGorrell kymograph operated at speed-P.

Aqueous solutions of all materials were employed in these studies.Essentially, the method consisted of initially standardizing submaximalcontractions of the isolated ileum to acetylcholine chloride, histaminephosphate, serotonin creatinine sulfate, and barium chloride. The testmaterial was then introduced into the bath and two minutes later theileum was again challenged with the various spasmogens. Tests were madeat various concentrations of the compounds in the bath until it was pos-5 sible to differentiate their relative activity as antagonists of thespasmogens.

The results of the pharmacological testing indicate that the compoundsare predominantly acetylcholine antagonists and are effective ininhibiting gastrointestinal motility in vivo and in vitro. In general,the compounds compared favorably in potency with methantheline bromideunder the conditions of these tests.

Various modifications may be made in the compounds of the presentinvention Without departing from the spirit and scope thereof, and it isto be understood that the invention is limited only by the scope of theappended claims.

I claim:

1. 1-ethyl-3-pyrrolidyl benzilate hydrochloride.

2. 1-ethyl-3-pyrrolidyl benzilate methobromide.

References Cited by the Examiner UNITED STATES PATENTS 2,792,339 5/1957Ekenstam et al. 260--326.3 2,816,895 12/1957 Ehrhart et al. 260294.3

6 2,844,591 7/ 1958 Feldkamp et al. 260-326.3 2,918,406 12/1959 Biel260294.3 2,918,407 12/ 1959 Biel 260294.3 2,918,408 12/ 1959 Biel260294.3 2,987,517 6/1961 Martin et a1. 260326.3 3,157,671 11/1964Bowman et al 260326.3

FOREIGN PATENTS 483,258 4/ 1938 Great Britain.

555,178 8/1957 Belgium.

159,630 7/1957 Sweden.

OTHER REFERENCES Richters Organic Chemistry, volume 3, pages 3 to 4(1923).

Biel et al.: J. Am. Chem. Society, lvolume 74, pages 1485-88 (1952).

ALEX MAZEL, Primary Examiner.

20 H. I. LIDOFF, Examiner.

JOSE TOVAR, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No.3,301,869 January 31, 1967 Carl D. Lu-nsford It is hereby certified thaterror appears in the above numbered patent requiring correction and thatthe said Letters Patent should read as corrected below.

Column 1, lines 20 to 26, the formula should appear as shown belowinstead of as in the patent: I

henyl phenyl-C-CO-Of-j R Signed and sealed this 28th day of November1967.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. EDWARD J BRENNER Attesting Officer Commissioner ofPatents

1. 1-ETHYL-3-PYRROLIDYL BENZILATE HYDROCHLORIDE.